Nanoparticles are used in a broad range of applications such as in vivo imaging technology, medical applications, gene transfer, drug delivery, diagnosis and treatment of diseases, etc. Specifically, nanoparticles are widely used in a variety of biomedical applications including, for example, a magnetic resonance imaging (MRI) contrast agent, cellular level therapy, hyperthermia, drug delivery, nucleic acid isolation, or the like, thereby increasing importance thereof.
The most important requirement for the application of nanoparticles in biomedical applications is primarily to ensure high quality nanoparticles and, in addition, to allow nanoparticles to have water-dispersion stability to stably maintain the nanoparticles in vivo. Here, a high quality nanoparticle may mean a nanoparticle with features of; (i) uniformity of particle size, (ii) easy control of particle size, (iii) excellent particle crystallinity, etc.
In order to accomplish satisfactory results in vitro and in vivo by applying such high quality nanoparticles to a human body and bioscience technologies, it is necessary to select a nanoparticle suitable to the characteristics of a specific application and, above all, a skill to treat nanoparticles with a bio-compatible material having excellent dispersibility.
Nanoparticles commercially available in the art are mostly synthesized by co-precipitation that controls pH in an aqueous system to precipitate the nanoparticles, or obtained by synthesis in a gas phase. However, nanoparticles generated by the foregoing processes are significantly agglomerated due to the lack of a stabilizer on the surface of the synthesized nanoparticles, and have difficulties in controlling a size of nanoparticle and preparing nanoparticles with a uniform size.
A method for synthesis of nanoparticles having a lipophilic surfactant adhered to the surface thereof by thermal decomposition of an inorganic precursor as well as the surfactant in an organic solvent at high temperature has recently been developed. This method has advantages in that size and shape of nanoparticles are preferably controlled, the synthesized nanoparticles show high uniformity in size and excellent crystallinity without agglomeration. However, the synthesized nanoparticles also have disadvantages in that, since a surfactant having hydrophobic properties is adhered the surface of the synthesized nanoparticles, these nanoparticles are not dispersed in water and are problematic when used in vivo. Therefore, in order to use such prepared inorganic nanoparticles in vivo, surface modification into a hydrophilic state is necessary. There are generally three kinds of methods for surface modification of hydrophobic nanoparticles into a hydrophilic state.
A first one is a ligand exchange method, wherein excess of ligands having functional groups bondable to the surface of nanoparticles are introduced to allow the ligands to be bonded at a site where the surfactant was detached.
A second one is an encapsulation method, wherein amphiphilic ligands are introduced to nanoparticles, in order to allow a hydrophobic portion of the amphiphilic ligand facing a surfactant part of the nanoparticle while a hydrophilic portion thereof is exposed to the outside, thus becoming hydrophilic. However, this method requires complicated experimental conditions since separate particles are surrounded with an amphiphilic material, and causes problems for mass production.
A third one is a method of using micelles wherein micelles are prepared in a solvent containing hydrophobic nanoparticles dispersed therein and the nanoparticles are introduced into the micelles. This method is characterized in that several nanoparticles are introduced into one micelle, thus causing a problem in preparing hydrophilic nanoparticles having a small hydrodynamic diameter. Moreover, a problem of causing breakage of micelles due to increase/decrease in a concentration of ions in vivo and/or a blood flow rate may be caused.
Accordingly, numerous studies have currently been executed to develop a novel method for hydrophilization of nanoparticles through ligand exchanging. However, it is important to suitably select a functional group enabling bonding of the ligand to the surface of nanoparticle that is combined with a surfactant. A chargeable functional group can generally bond well to the surface of a nanoparticle and examples thereof may mostly include amines, phosphates, sulfates, carboxylate, etc.
In general, hydrophilized nanoparticles may have dispersion stability in water depending upon characteristics of hydrophilic materials. In the case of a single molecule, nanoparticles are not cohered due to repulsion caused by charge of molecules, instead, maintain water-dispersibility. However, the nanoparticles may be cohered with a change of pH, thus having inferior dispersion stability in vivo. Therefore, hydrophilization of nanoparticles including surface modification using ligands with relatively large molecular weight and utilizing van-der-Waals force has currently been studied. However, the nanoparticles hydrophilized by ligands having a large molecular weight entail problems such as a large hydrodynamic diameter and difficulties in ligand exchanging when the molecular weight is increased.
Moreover, preparation of bio-compatible ligands needs a complicated manufacturing process and entails a difficulty in mass production thereof.
In recent years, a water dispersion method of nanoparticles using a polymer comprising of phosphine oxide and polyethyleneglycol (PEG) has been disclosed in, for example, “Versatile PEG-derivatized Phosphine Oxide Ligands for Water-Dispersible Metal Oxide Nanocrystals,” by Hyon Bin Na, In Su Lee, Heon Jin Seo, Yong Il Park, Jung Hee LEE, Sang Wook Kim and Taeghwan Hyeon (Chem. Comm., 2007, 5167). Alternatively, a method that includes reacting methoxy polyethyleneglycol with phosphoryl chloride (POCl3) to synthesize PO-PEG ligand, ligand exchanging the synthesized PO-PEG ligand with nanoparticles in an organic solvent and dispersing the same in water, has been disclosed. Although this method adopts a relatively simple manufacturing process, phosphoryl chloride (POCl3) readily contacts oxygen to be oxidized in the preparation of ligands, thus causing difficulties in processing such as a requirement for synthesis in an inert atmosphere such as argon or nitrogen. Furthermore, one to three polyethyleneglycols are bonded to a phosphoryl group in the preparation of ligands, thus having a problem in preparing reproducible ligands.